High-throughput screening (HTS) of small molecule libraries is a powerful technique to identify new chemical probes and therapeutic leads. However, the stereochemical and molecular diversity of current libraries is lacking. Recognizing that new synthetic methods catalyze discoveries in biomedical research, the long-term goal of this research program is to develop highly efficient methods for the synthesis of biologically active molecules. The objective of this subproject is to establish new enabling reaction technologies to build novel scaffolds with significant molecular and stereochemical complexity and to exploit these methods to prepare diverse compound libraries. On the basis of strong preliminary results, the new methods for diversity oriented synthesis are proposed in three specific aims: (1) development of copper-catalyzed alkylation of nitroalkanes as a platform for library synthesis; (2) establishment of palladium-catalyzed cross couplings of 0-acylaldoximes to enable preparation of highly substituted piperidine libraries via an aza-Suzuki/[4+2] cascade strategy; and (3) development of copper-catalyzed arylation of chromene acetals to deliver libraries of a-aryl chromenes. Each of these technologies is innovative, allowing new entries and greatly facilitated access to complex nitroalkanes, piperidines and chromenes, as well as many derivatives of these highly versatile intermediates. The proposed work is significant, because it will establish new routes for efficient synthesis of bioactive compounds, provide novel libraries to HTS campaigns, and create the synthetic infrastructure and highly interactive collaborations necessary to not only identify hit compounds, but also to progress these hits into useful chemical probes and leads for therapeutic development.